The expression of β-lactamases is the most common cause of resistance to β-lactam antibiotics (i.e. beta-lactam containing antibiotics), such as penicillins and cephalosporins. (Livermore, D. M., Curr. Protein Pept. Sci. 2009, 10, 397-400; Fisher, J. F. et al., Chem. Rev. 2005, 105, 395-424; Paterson, D. L. and Bonomo, R. A., Clin. Microbiol. Rev. 2005, 18, 657-686) β-Lactamases catalyze the hydrolysis of the critical β-lactam ring in β-lactam antibiotics, thereby inactivating them. (Wilke, M. S. et al., Curr. Opin. Microbiol. 2005, 8, 525-533) To overcome this problem, β-lactamase inhibitors, such as clavulanic acid or sulbactam, are co-administered with the primary β-lactam (FIG. 1). (Lode, H. M., Int. J. Antimicrob. Agents 2008, 32, 10-28; Drawz, S. M. and Bonomo, R. A., Clin. Microbiol. Rev. 2010, 23, 160-201) However, the active core of these inhibitors remains a β-lactam ring, enabling the rapid development of resistance. (Bebrone, C. et al., Drugs 2010, 70, 651-679) For example, AmpC, a class C β-lactamase expressed by many nosocomial pathogens, is not inhibited by clavulanic acid or sulbactam, leading to substantial problems in the clinic. (Bush, K., Curr. Pharm. Des. 1999, 5, 839-845; Jacoby, G. A., Clin. Microbiol. Rev. 2009, 22, 161-182)
Inhibitors of β-lactamases can be used in combination with primary β-lactam antibiotics to help overcome bacterial resistance to antibiotics. An example of one of three such now on the market is Amoxicillin/Clavulanate (Augmentin), widely used empirically to treat bacteria resistant to penicillin and first generation cephalosporins via the action of a class A β-lactamase, such as TEM-1. A liability of the β-lactamase inhibitor drug, clavulanate, is that resistant forms of TEM-1 have evolved that can hydrolyze it (IRTs such as TEM-30, for instance), and its use has promoted the spread of β-lactamases natively resistant to its actions (e.g., class C β-lactamases like AmpC, and the metalo-β-lactamases). Clavulanate affords no protection to cephalosporins clinically, and has never been combined, for instance, with the 3rd generation cephalosporins (e.g., ceftazidime), leaving these widely used drugs susceptible to the evolution of the extended spectrum β-lactamases (ESBLs). Provided herein are solutions to these and other problems in the art.